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psx:substance/caffeine/search/7aeae4b6-0532-42c8-b19e-102b1a524bd4

search2026-04-25recordweb_search

derived from · upstream

none recorded

feeds · downstream

Closure of psx:substance/caffeine/search/7aeae4b6-0532-42c8-b19e-102b1a524bd4: 72 upstream, 127 downstream.

psx:substance/caffeine/search/7aeae4b6-0532-42c8-b19e-102b1a524bd4
  ├─ used  search/2d1f52b6-c23f-4dd3-b9f6-1f74f7854728  Searched PubChem for "caffeine"
  ├─ used  search/d0484f5c-de07-470a-ab51-833db75d73b4  Searched PubMed for "caffeine adenosine receptor antagonist mechanism of action pharmacology"
  ├─ used  search/7dbde8dc-c8e5-415d-9c9e-05bd0bab1f8e  Searched OpenAlex for "caffeine pharmacology adenosine receptor"
  ├─ used  search/2c31d51b-1dfb-4bd6-9397-749e38558452  Searched PubMed for "caffeine pharmacokinetics half-life metabolism CYP1A2 human"
  ├─ used  search/84da1eca-6463-4b40-884a-0d45de7a8a02  Searched PubMed for "caffeine adenosine A1 A2A receptor binding affinity Ki antagonist"
  ├─ used  search/da42d53b-8355-4a8a-937d-9e283b5029af  Searched OpenAlex for "caffeine adenosine receptor antagonist central nervous system stimulant"
  ├─ used  search/d8061162-0461-408e-a4f9-a6f725ffd430  Searched PubMed for "caffeine toxicity overdose lethal dose LD50 case report"
  ├─ used  search/ead81512-e7af-4418-8f67-54f780ecab7c  Searched PubMed for "caffeine dependence withdrawal syndrome physical psychological"
  ├─ used  search/6e7d747e-1b70-4ba3-951e-c793e1268709  Searched PubMed for "PMID 21303899, 20164566, 35280254"
  ├─ used  search/74e47237-9c0b-4076-837f-ef1e34aaa320  Searched PubMed for "caffeine toxicity overdose lethal dose LD50 case report"
  ├─ used  search/422c9165-e27d-42ab-9a9e-9795f61c9dd3  Searched PubMed for "caffeine dependence withdrawal syndrome"
  ├─ used  search/c7200371-fa0c-4be1-9e18-8e05fd64cafa  Searched OpenAlex for "caffeine pharmacology Fredholm review xanthine stimulant"
  ├─ used  search/7967cf31-2e77-4da4-937e-3486f60d90c8  Searched PubMed for "Fredholm caffeine xanthines pharmacological actions review"
  ├─ used  search/98c3ee81-c02d-4a9d-b4f7-f9878dfc349d  Searched PubMed for "caffeine sleep quality adenosine polysomnography"
  ├─ used  search/c71d7c96-da2e-47f6-b12d-be14b44ef65c  Searched PubMed for "caffeine Parkinson disease neuroprotection epidemiology risk"
  ├─ used  search/dcee54e2-31de-42fe-b2b9-390fb82dbf8d  Searched ClinicalTrials.gov for "caffeine cognitive performance randomized controlled trial"
  ├─ used  search/3ad48c20-4d3d-4bb0-ab16-e65830d6f640  Searched PubMed for "caffeine anxiety panic disorder anxiogenic"
  ├─ used  search/054b8baa-6a07-4dd3-aab1-a959544c04ec  Searched WebSearch for "caffeine legal status FDA GRAS worldwide regulatory"
  ├─ used  search/84bb27c9-c68c-4fee-8785-00b79497a406  Searched WebSearch for "caffeine melting point solubility water pKa physical chemical properties"
  ├─ used  search/14ac497b-4270-4b9c-82b6-90ec66b5ae25  Searched PubMed for "caffeine adenosine A1 A2A receptor crystal structure xanthine binding"
  ├─ used  search/8cbd9de4-df12-4006-9d71-a21eee13d7a9  Searched PubMed for "caffeine fluvoxamine CYP1A2 drug interaction"
  ├─ used  search/07d8d88a-a65b-4627-8a9c-fd7b3dddecee  Searched PubMed for "caffeine Alzheimer dementia risk"
  ├─ used  search/2a90d139-b9ba-4d0d-a6aa-ea377b529ad1  Searched PubMed for "PMID 22671762 caffeine MDMA interaction"
  ├─ used  search/7dc42f3f-8ac3-4fcb-aaf1-82c4672a4cc8  Searched PubMed for "caffeine alcohol energy drink combination"
  ├─ used  search/eb9f4b75-cd8a-4009-a5b1-c16ed978d3cf  Searched Crossref/verify_doi for "DOI 10.1186/s12970-020-00383-4 and 10.1111/j.1476-5381.2012.02065.x"
  ├─ used  search/4e2e9c69-ed99-424f-aa75-082659221ccc  Searched WebSearch for "EFSA 2015 caffeine safety assessment 400 mg per day"
  ├─ used  search/e4540959-a014-4f45-83d1-a5bc959be949  Searched PubMed for "caffeine paraxanthine theobromine theophylline metabolites CYP1A2"
  ├─ used  search/a729bb8e-7513-4310-97d2-1050d56a8ce7  Searched PubMed for "cigarette smoking CYP1A2 induction caffeine clearance"
  ├─ used  search/5ee27838-1e34-4f34-95c4-09840bcc69fc  Searched cross-reference for "Primary ROA discrepancy: seed data says insufflated, evidence review"
    ├─ used  src/pmid:10049999  Actions of caffeine in the brain with special reference to factors that contribute to its widespread use.
    ├─ used  src/doi:10.3389/fphar.2021.752826  Pharmacokinetics of Caffeine: A Systematic Analysis of Reported Data for Application in Metabolic Phenotyping and Liver Function Testing.
    ├─ used  src/url:82c6fbbe1c91abad  Caffeine history: isolation by Runge 1819, synthesis by Fischer 1895
    ├─ used  src/doi:10.1212/WNL.0000000000209201
    ├─ used  src/doi:10.1056/nejmoa054065  Caffeine therapy for apnea of prematurity.
    ├─ used  src/doi:10.1124/pr.110.003285  International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update.
    ├─ used  src/doi:10.1016/j.mam.2016.11.011  Low, but not high, dose caffeine is a readily available probe for adenosine actions.
    ├─ used  src/doi:10.3233/JAD-2010-1408
    ├─ used  src/doi:10.3233/JAD-2010-1378
    ├─ used  src/doi:10.1016/j.genhosppsych.2021.11.005  Effects of caffeine on anxiety and panic attacks in patients with panic disorder: A systematic review and meta-analysis.
    ├─ used  src/doi:10.1016/j.ajem.2019.09.018  Acute intentional caffeine overdose treated preemptively with hemodialysis.
    ├─ used  src/doi:10.2174/1570159x13666141210215655  Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug?
    ├─ used  src/doi:10.1016/j.hrthm.2024.02.018  Sudden cardiac arrest occurring in temporal proximity to consumption of energy drinks.
    ├─ used  src/doi:10.3390/nu16183048  Caffeine Withdrawal
    ├─ used  src/doi:10.1523/jneurosci.3574-05.2006  Presynaptic Control of Striatal Glutamatergic Neurotransmission by Adenosine A1-A2A Receptor Heteromers
    ├─ used  src/doi:10.1016/j.pnpbp.2019.109851  Caffeine-dependent changes of sleep-wake regulation: Evidence for adaptation after repeated intake.
    ├─ used  src/pmid:8807660  A fluvoxamine-caffeine interaction study.
    ├─ used  src/pmid:8054245  Biotransformation of caffeine in human liver microsomes from foetuses, neonates, infants and adults.
    ├─ used  src/pmid:2519  Caffeine — PubChem CID 2519
    ├─ used  src/url:dd3ceb5d8ca5d8cc  Caffeine physical properties: melting point, solubility, CAS
    ├─ used  src/doi:10.3233/JAD-2010-1379
    ├─ used  src/pmid:7960313  Caffeine and sports activity: a review.
    ├─ used  src/pmid:16135658  Oxidation of caffeine by CYP1A2: isotope effects and metabolic switching.
    ├─ used  src/pmid:10427467  Drug interactions with tobacco smoking. An update.
    ├─ used  src/doi:10.1016/j.str.2011.06.014  Structure of the adenosine A(2A) receptor in complex with ZM241385 and the xanthines XAC and caffeine.
    ├─ used  src/pmid:11907488  Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (CYP1A2) and omeprazole (CYP2C19).
    ├─ used  src/pmid:16236038  Fluvoxamine impairs single-dose caffeine clearance without altering caffeine pharmacodynamics.
    ├─ used  src/doi:10.1016/S1474-4422(16)30230-7
    ├─ used  src/doi:10.3390/nu14091697  Plasma Caffeine Levels and Risk of Alzheimer's Disease and Parkinson's Disease: Mendelian Randomization Study.
    ├─ used  src/doi:10.1039/d4fo01750a  Tea, coffee, and caffeine intake and risk of dementia and Alzheimer's disease: a systematic review and meta-analysis of cohort studies.
    ├─ used  src/doi:10.1038/s41598-021-83504-6  Caffeine may disrupt the impact of real-time drowsiness on cognitive performance: a double-blind, placebo-controlled small-sample study.
    ├─ used  src/doi:10.1186/s12970-020-00383-4  International society of sports nutrition position stand: caffeine and exercise performance.
    ├─ used  src/doi:10.1111/ejn.70511  The Effect of Caffeine Consumption and Acute Withdrawal on Resting-State fMRI Brain Connectivity, Mood and Cognition.
    ├─ used  src/doi:10.1371/journal.pone.0108782  Expression and characterization of purinergic receptors in rat middle meningeal artery--potential role in migraine.
    ├─ used  src/doi:10.1111/jce.13210  Arrhythmogenic effects of energy drinks.
    ├─ used  src/doi:10.1111/nure.12136  Regulatory status of caffeine in the United States.
    ├─ used  src/doi:10.1007/s10654-014-9944-x  Caffeine intake during pregnancy and adverse birth outcomes: a systematic review and dose-response meta-analysis.
    ├─ used  src/doi:10.2903/j.efsa.2015.4102  Scientific Opinion on the safety of caffeine. EFSA 2015.
    ├─ used  src/pmid:8089887  Caffeine dependence syndrome. Evidence from case histories and experimental evaluations.
    ├─ used  src/doi:10.1037/a0027246  Characterization of individuals seeking treatment for caffeine dependence.
    ├─ used  src/doi:10.1111/j.1476-5381.2012.02065.x  Caffeine provokes adverse interactions with MDMA and related psychostimulants: mechanisms and mediators.
    ├─ used  src/doi:10.1007/s00213-012-2677-1  The effects of energy drink in combination with alcohol on performance and subjective awareness.
    └─ generated_by  pub/2f054361-f59f-490c-88b5-e2affe5330f4  Publication — backfill
├─ used  gen/9b88d939-477d-4a2d-9fe9-8f2071545074  Generation — pipeline-v5
  ├─ derived_from  version/1  Revision 1
    ├─ derived_from  issue/notice@fb6e5e61c982  Issued notice
    ├─ derived_from  issue/info_card@471af3eb6a45  Issued info_card
    ├─ derived_from  issue/emergency@777b5863d801  Issued emergency
    ├─ derived_from  issue/info_card@0143f403def8  Issued info_card
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      ├─ used  claim/da510b5b-d0cd-4df7-a165-4e6531cf0df2  Claim in pharmacokinetic-detail — supported
      ├─ used  claim/a3a8cac9-a222-479b-ab37-eb173a93f28d  Claim in safety — supported
      ├─ used  claim/1df774fe-4d0c-487c-b7a5-2357e968d707  Claim in clinical-evidence — supported
      ├─ used  claim/a356f31a-2434-418b-bd69-9ffa53629b16  Claim in neuroscience — supported
      ├─ used  claim/61da2cc4-82d5-42ab-b949-1f9084a3c644  Claim in clinical-evidence — supported
      ├─ used  claim/f5201db1-9b6b-463d-aba2-471720c3abc9  Claim in neuroscience — supported
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      ├─ used  claim/accb5910-eff3-4861-ac77-84a22fd22265  Claim in neuroscience — supported
      ├─ used  claim/71d48125-f783-480c-bbe9-1773ce1bff6c  Claim in clinical-evidence — supported
      ├─ used  claim/85409ac3-ed03-4ec6-87f3-99aca4fe3896  Claim in clinical-evidence — supported
      ├─ used  claim/a634651f-4c38-462b-9061-8054dcb92d94  Claim in neuroscience — inconclusive  working
      ├─ used  claim/3e67054e-60b0-4f89-a446-ea36651be3a2  Claim in safety — supported
      ├─ used  claim/340cb9a4-249e-4c79-b0fe-5d21ab76de36  Claim in safety — supported
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      └─ used  claim/0b10fc24-0104-4642-9396-eba6a6adc6ba  Claim in safety — inconclusive  working
… closure truncated at 200 nodes

indented by distance from this node, not by parentage

1Provenance card

the boundary, as counts

Sources

4230 with DOI

14 strong · 22 moderate · 6 weak

Compilations

22026-04-25T19:20:50.901Z

pipeline-v5 · prompt hash not recorded — run predates 2026-09 · 10 other runs

Decisions

32last ruled 2026-06-04

0 awaiting a ruling

Issued documents

42026-10-19T20:30:58.544Z

notice · info card · emergency

Searches

302 with no results

queries and counts on the build

Claims checked

13385 supported

85 supported · 48 not

Correspondence

0received

consent field ships in Phase 4

Edges

382

derivations recorded for this entity

Complete over 42 sources, 2 compilations, and 32 decisions.Not here: the private journal (never).Working material — drafts, discards, unsupported claims — is listed below and readable on the working page.Cite: psychedex.org/substances/caffeine/archive

2Build

one panel per compilation run

generation run 2026-04-25

5 min failedmodel not recordedplan not recordedrun/f795b6c5…

research

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Selection

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consumed as sources42

Verification

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not supported0
inconclusive0
  • record
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The model's own caveats

none raised on this run

Reproduce

inputs
42 source keys (listed under Sources)
plan
not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
model
not recorded
streams
none — agent transcripts are persisted from 2026-09 onward

generation run 2026-04-25

83 min completedmodel pipeline-v5plan not recordedrun/e3420542…

research

citationsRegistryrecordresearchOutputworking

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verificationResultworking

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publish

runMetarecordrunSummaryrecord

Selection

results seen155
selected by the model48
consumed as sources42

Verification

claims checked133
supported85
partially supported0
not supported0
inconclusive48
  • record
  • seen / partial
  • working

The model's own caveats

  • taper_silent

Reproduce

inputs
42 source keys (listed under Sources)
plan
not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
model
pipeline-v5
streams
none — agent transcripts are persisted from 2026-09 onward
30 searches — query, source, results, what was kept and why
30 searches for this run
#sourcequeryseenkeptrationale
1PubMedcaffeine pharmacokinetics half-life metabolism CYP1A2 human101—
2PubChemcaffeine11Primary chemical identity verification
3OpenAlexcaffeine pharmacology adenosine receptor100—
4PubMedcaffeine adenosine A1 A2A receptor binding affinity Ki antagonist40—
5PubMedcaffeine adenosine receptor antagonist mechanism of action pharmacology101—
6PubMedcaffeine toxicity overdose lethal dose LD50 case report11—
7OpenAlexcaffeine adenosine receptor antagonist central nervous system stimulant84—
8PubMedcaffeine dependence withdrawal syndrome physical psychological63—
9WebSearchcaffeine legal status FDA GRAS worldwide regulatory102—
10PubMedcaffeine Alzheimer dementia risk62—
11PubMedcaffeine adenosine A1 A2A receptor crystal structure xanthine binding11—
12PubMedcaffeine anxiety panic disorder anxiogenic31—
13PubMedcaffeine dependence withdrawal syndrome63—
14PubMedPMID 21303899, 20164566, 3528025433—
15PubMedcaffeine toxicity overdose lethal dose LD50 case report11—
16PubMedFredholm caffeine xanthines pharmacological actions review52—
17WebSearchcaffeine discovery history 1819 Runge isolation Fischer synthesis xanthine102—
18WebSearchcaffeine melting point solubility water pKa physical chemical properties102—
19PubMedcaffeine fluvoxamine CYP1A2 drug interaction52—
20PubMed · absencecaffeine sleep quality adenosine polysomnography00—
21PubMedcaffeine Parkinson disease neuroprotection epidemiology risk62—
22OpenAlexcaffeine pharmacology Fredholm review xanthine stimulant84—
23ClinicalTrials.govcaffeine cognitive performance randomized controlled trial82—
24PubMedPMID 22671762 caffeine MDMA interaction11—
25WebSearchEFSA 2015 caffeine safety assessment 400 mg per day101—
26cross-reference · absencePrimary ROA discrepancy: seed data says insufflated, evidence review00—
27PubMedcaffeine alcohol energy drink combination31—
28PubMedcigarette smoking CYP1A2 induction caffeine clearance21—
29PubMedcaffeine paraxanthine theobromine theophylline metabolites CYP1A252—
30Crossref/verify_doiDOI 10.1186/s12970-020-00383-4 and 10.1111/j.1476-5381.2012.02065.x22—
133 claims by section — every cited sentence, checked against its source
safety43 · 35 ok

  • Because CYP1A2 mediates ~95% of caffeine metabolism, any potent CYP1A2 inhibitor dramatically increases caffeine exposure. Fluvoxamine is the most clinically significant: standard therapeutic doses increase caffeine half-life from approximately 5 hours to 31 hours, with total clearance reduced 5-foldsupported

    Fluvoxamine co-administration impairs caffeine clearance and prolongs elimination half-life via CYP1A2 inhibition. pmid:16236038

  • Abuse potential is low — caffeine does not produce the behavioral reinforcement profile of classic drugs of abuse, though it acts as a weak reinforcer.supported

    Covers adenosine antagonism, dopaminergic effects, reinforcement, withdrawal, tolerance. pmid:10049999

  • The estimated human LD50 is approximately 150–200 mg/kg body weight — roughly 10.5–14 g for a 70 kg adult, equivalent to approximately 80–100 cups of brewed coffeesupported

    LD50 stated as 150-200 mg/kg; lethal plasma levels ~80-100 ug/mL (~10g ingestion). j.ajem.2019.09.018

  • Claim in safety — inconclusiveinconclusiveworking →

  • The caffeine overdose toxidrome progresses dose-dependently:supported

    Tachyarrhythmias, hemodynamic instability. Pre-dialysis caffeine level 254 ug/mL. j.ajem.2019.09.018

  • The caffeine overdose toxidrome progresses dose-dependently:supported

    Review of caffeine mechanisms... use, abuse, dependence, intoxication, lethal effects. 1570159x13666141210215655

  • Kohl et al. reported a 39-year-old male who intentionally ingested 50 g of caffeine (pre-dialysis plasma level: 254 ug/mL) — approximately 2.5 times the lethal plasma thresholdsupported

    Case report: 39-year-old male ingested 50g caffeine. Lethal plasma levels ~80-100 ug/mL. Pre-dialysis caffeine level 254 ug/mL. j.ajem.2019.09.018

  • Claim in safety — inconclusiveinconclusiveworking →

  • Caffeine induces cerebral vasoconstriction — a property exploited therapeutically in headache and migraine treatmentsupported

    Caffeine (as adenosine receptor antagonist) inhibits adenosine-mediated relaxation in middle meningeal artery, providing molecular mechanism for caffeine's utility as cranial pain/headache adjuvant. journal.pone.0108782

  • At high doses, particularly in the context of energy drink consumption, caffeine can provoke tachyarrhythmias via cardiac calcium overload and catecholamine surgesupported

    Two case reports of life-threatening ventricular arrhythmias in young patients after energy drink consumption. jce.13210

  • Martinez et al. documented sudden cardiac arrest in young adults temporally associated with energy drink consumption.supported

    Documents cases of sudden cardiac arrest in temporal proximity to consumption of energy drinks. j.hrthm.2024.02.018

  • Claim in safety — inconclusiveinconclusiveworking →

  • Greenwood et al.'s meta-analysis (60 publications) quantified dose-dependent pregnancy risks per 100 mg daily caffeine increment:supported

    Meta-analysis of 60 publications: per 100mg caffeine increment associated with 14% increased spontaneous abortion risk, 19% stillbirth, 7% low birth weight, 10% SGA. s10654-014-9944-x

  • Current guidelines recommend <=200 mg/day during pregnancy.supported

    For pregnant women: up to 200mg/day safe. j.efsa.2015.4102

  • Caffeine has dose-dependent anxiogenic properties:supported

    High doses can induce psychotic/manic symptoms. Panic disorder patients particularly sensitive to anxiogenic effects. jad-2010-1378

  • Caffeine has dose-dependent anxiogenic properties:supported

    Systematic review and meta-analysis of caffeine's anxiogenic and panicogenic effects in panic disorder patients. Quantifies magnitude and dose-response relationships. j.genhosppsych.2021.11.005

  • Very high doses: Rare psychotic or manic symptoms have been reportedsupported

    High doses can induce psychotic/manic symptoms. jad-2010-1378

  • Patients with panic disorder are particularly sensitive — caffeine challenge reliably provokes panic attacks in this populationsupported

    Systematic review and meta-analysis of caffeine's anxiogenic and panicogenic effects in panic disorder patients. j.genhosppsych.2021.11.005

  • The anxiogenic threshold is influenced by ADORA2A polymorphism (A2A receptor gene variant), with certain genotypes showing heightened vulnerability.supported

    A2A receptor polymorphism influences anxiety threshold. jad-2010-1378

  • Caffeine withdrawal symptoms can closely mimic psychiatric disorders (anxiety, depression, cognitive impairment), representing a documented source of clinical misdiagnosis.supported

    Symptoms: headache, fatigue, irritability, mood changes. Regular use produces physical and psychological dependence. nu16183048

  • Tolerance develops to many of caffeine's effects with regular use, particularly psychomotor/locomotor stimulationsupported

    Covers adenosine antagonism, dopaminergic effects, reinforcement, withdrawal, tolerance. pmid:10049999

  • The molecular mechanism involves upregulation of adenosine receptors and functional adaptation of A1-A2A heteromers in the striatumsupported

    Caffeine acts on A1-A2A heteromers; chronic caffeine leads to tolerance through modifications in heteromer function. jneurosci.3574-05.2006

  • Tolerance to wakefulness-promoting effects is incomplete — caffeine remains wake-promoting even in chronic users, though the effect is blunted compared to the caffeine-naive state.supported

    Daily caffeine intake and withdrawal affect circadian rhythms and wake-promotion. Evidence for adaptation after repeated intake. j.pnpbp.2019.109851

  • Caffeine dependence is recognized in the DSM-5 as Caffeine Use Disorder (designated for further study), with Caffeine Withdrawal as a fully diagnosable conditionsupported

    Review of caffeine withdrawal as DSM-5 recognized condition. nu16183048

  • Strain et al. established the caffeine dependence syndrome using DSM-IV criteria in 1994supported

    Assessment of caffeine dependence syndrome using DSM-IV generic criteria for substance dependence. Landmark JAMA paper establishing caffeine dependence syndrome. pmid:8089887

  • Juliano et al. characterized 94 treatment-seeking individuals: 93% met DSM-IV substance dependence criteria, with mean daily intake of 548 mg; withdrawal (96%), persistent desire or unsuccessful efforts to control use (89%), and continued use despite problems (87%) were the most prevalent criteria.supported

    94 subjects seeking caffeine dependence treatment; mean 548 mg/day intake; 93% met DSM-IV substance dependence criteria. Withdrawal (96%), persistent desire to control use (89%), use despite problems (87%). a0027246

  • Lethal plasma concentration is approximately 80–100 ug/mL.supported

    Lethal plasma levels ~80-100 ug/mL (~10g ingestion). j.ajem.2019.09.018

  • Caffeine withdrawal syndrome (DSM-5 recognized):supported

    Review of caffeine withdrawal as DSM-5 recognized condition. Symptoms: headache, fatigue, irritability, mood changes. nu16183048

  • Mechanism: Withdrawal headache results from rebound cerebral vasodilation following cessation of caffeine-mediated vasoconstrictionsupported

    Caffeine (as adenosine receptor antagonist) inhibits adenosine-mediated relaxation in middle meningeal artery, providing molecular mechanism for caffeine's utility as cranial pain/headache adjuvant. journal.pone.0108782

  • Because CYP1A2 mediates ~95% of caffeine metabolism, any potent CYP1A2 inhibitor dramatically increases caffeine exposure. Fluvoxamine is the most clinically significant: standard therapeutic doses increase caffeine half-life from approximately 5 hours to 31 hours, with total clearance reduced 5-foldsupported

    Fluvoxamine 50-100mg/day increases caffeine half-life from 5h to 31h and reduces total clearance from 107 to 21 ml/min. pmid:8807660

  • Even low-dose fluvoxamine (10–20 mg/day) substantially inhibits caffeine metabolismsupported

    Even low therapeutic doses of fluvoxamine significantly inhibit CYP1A2 activity as measured by caffeine metabolic ratio. pmid:11907488

  • Claim in safety — inconclusiveinconclusiveworking →

  • CYP1A2 inducers — principally tobacco smoke (via polycyclic aromatic hydrocarbons) — accelerate caffeine clearance by 40–65%supported

    Polycyclic aromatic hydrocarbons in tobacco smoke induce CYP1A2, leading to faster caffeine clearance. pmid:10427467

  • Claim in safety — inconclusiveinconclusiveworking →

  • Vanattou-Saifoudine et al. conducted the most comprehensive review of caffeine-psychostimulant interactions, finding that caffeine profoundly enhances MDMA toxicity in preclinical models: dramatically increased hyperthermia, tachycardia, cardiovascular toxicity, mortality, and enhanced long-term serotonergic neurotoxicitysupported

    Caffeine co-administration profoundly enhances acute MDMA toxicity: hyperthermia, tachycardia, increased mortality in rats. Enhances long-term serotonergic neurotoxicity of MDMA. j.1476-5381.2012.02065.x

  • Similar enhancement of toxicity applies to cocaine, d-amphetamine, and ephedrine combinations via the same adenosine/PDE pathways.supported

    Same mechanism implicated with cocaine, d-amphetamine, and ephedrine. Mechanism: MDMA-dopamine release + caffeine adenosine antagonism + PDE inhibition. j.1476-5381.2012.02065.x

  • Caffeine partially masks subjective alcohol intoxication but does not reduce blood alcohol concentration or actual psychomotor impairmentsupported

    Energy drink + alcohol study: caffeine masks subjective intoxication but does not reduce blood alcohol or objective performance impairment. s00213-012-2677-1

  • Panic disorder and anxiety disorders: Caffeine reliably provokes panic attacks in patients with panic disorder and exacerbates generalized anxietysupported

    Systematic review and meta-analysis of caffeine's anxiogenic and panicogenic effects in panic disorder patients. j.genhosppsych.2021.11.005

  • Claim in safety — inconclusiveinconclusiveworking →

  • Claim in safety — inconclusiveinconclusiveworking →

  • Pregnancy: Dose-dependent risks for spontaneous abortion, stillbirth, and low birth weight with no identifiable safe threshold below 200 mg/day.supported

    Meta-analysis of 60 publications: per 100mg caffeine increment associated with 14% increased spontaneous abortion risk, 19% stillbirth, 7% low birth weight. No identifiable threshold below which associations are absent. s10654-014-9944-x

  • CYP1A2 inhibitor co-administration: Patients on fluvoxamine, ciprofloxacin, or other potent CYP1A2 inhibitors face dramatically elevated caffeine exposure and should reduce intake proportionally.supported

    Warns of caffeine intoxication risk during fluvoxamine treatment. Fluvoxamine 50-100mg/day increases caffeine half-life from 5h to 31h. pmid:8807660

  • Claim in safety — inconclusiveinconclusiveworking →

pharmacology29 · 14 ok

  • Caffeine acts as a non-selective, competitive antagonist at all four adenosine receptor subtypes (A1, A2A, A2B, A3), with the A1 and A2A subtypes bearing the greatest pharmacological significance in the central nervous system at physiological concentrationssupported

    Caffeine causes biological effects via antagonizing all types of adenosine receptors (A1, A2A, A3, A2B). jad-2010-1379

  • Caffeine acts as a non-selective, competitive antagonist at all four adenosine receptor subtypes (A1, A2A, A2B, A3), with the A1 and A2A subtypes bearing the greatest pharmacological significance in the central nervous system at physiological concentrationssupported

    Reviews A1, A2A, A2B, A3 receptors including binding affinities, agonists, antagonists. pr.110.003285

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • By blocking adenosine's tonic inhibitory regulation, caffeine produces disinhibition of adenosine-suppressed neurotransmission — particularly in the dopaminergic and glutamatergic systems.supported

    Covers adenosine antagonism, dopaminergic effects, reinforcement, withdrawal, tolerance. pmid:10049999

  • Caffeine's pharmacological profile is explicitly dose-dependent:supported

    Low-dose caffeine acts as an adenosine A1, A2A, A2B antagonist. High-dose effects have different underlying mechanisms. j.mam.2016.11.011

  • High doses (>500–1000 mg): Additional mechanisms become pharmacologically relevant — phosphodiesterase (PDE) inhibition (PDE1, PDE4, PDE5) elevating intracellular cAMP and cGMP, and direct calcium mobilization from sarcoplasmic/endoplasmic reticulum stores via ryanodine receptors, contributing to positive inotropic and chronotropic cardiac effects.supported

    Three main mechanisms at cellular level: intracellular Ca2+ mobilization, PDE inhibition (cAMP increase), adenosine receptor antagonism. Main in vivo mechanism at normal doses is adenosine antagonism. pmid:7960313

  • High doses (>500–1000 mg): Additional mechanisms become pharmacologically relevant — phosphodiesterase (PDE) inhibition (PDE1, PDE4, PDE5) elevating intracellular cAMP and cGMP, and direct calcium mobilization from sarcoplasmic/endoplasmic reticulum stores via ryanodine receptors, contributing to positive inotropic and chronotropic cardiac effects.supported

    Also inhibits phosphodiesterases (PDE1, PDE4, PDE5), promotes calcium release from intracellular stores. jad-2010-1379

  • High doses (>500–1000 mg): Additional mechanisms become pharmacologically relevant — phosphodiesterase (PDE) inhibition (PDE1, PDE4, PDE5) elevating intracellular cAMP and cGMP, and direct calcium mobilization from sarcoplasmic/endoplasmic reticulum stores via ryanodine receptors, contributing to positive inotropic and chronotropic cardiac effects.supported

    Three main mechanisms at cellular level: intracellular Ca2+ mobilization, PDE inhibition (cAMP increase), adenosine receptor antagonism. pmid:7960313

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Ciruela et al. demonstrated that caffeine acts on A1R-A2AR heteromers in striatal glutamatergic terminals, providing a molecular mechanism for caffeine's modulation of glutamate releasesupported

    Demonstrates A1R-A2AR heteromers in striatal glutamatergic nerve terminals. Caffeine acts on A1-A2A heteromers. jneurosci.3574-05.2006

  • Dopamine: Elevated dopaminergic tone (particularly via A2A-D2 antagonism in striatum) underlies locomotor activation, mood enhancement, and weak reinforcement.supported

    Covers adenosine antagonism, dopaminergic effects, reinforcement, withdrawal, tolerance. pmid:10049999

  • Glutamate: Modulation via release of A1-mediated presynaptic inhibition influences excitability and memory consolidation.supported

    Demonstrates A1R-A2AR heteromers in striatal glutamatergic nerve terminals. Caffeine acts on A1-A2A heteromers. jneurosci.3574-05.2006

  • GABA: Inhibitory effects on GABA-A receptors reported at high concentrations.supported

    Also inhibits phosphodiesterases (PDE1, PDE4, PDE5), promotes calcium release from intracellular stores, and interferes with GABA-A receptors. jad-2010-1379

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Caffeine is almost exclusively metabolized in the liver by CYP1A2, which mediates ~95% of caffeine clearance via N-demethylation and C-8 hydroxylationsupported

    CYP1A2-mediated caffeine metabolism: nondissociative mechanism, N-3 demethylation to paraxanthine is primary pathway. pmid:16135658

  • The caffeine/paraxanthine plasma ratio serves as a validated in vivo phenotyping probe for CYP1A2 activity.supported

    Systematic analysis of caffeine pharmacokinetics from 141 publications... Application in Metabolic Phenotyping and Liver Function Testing. fphar.2021.752826

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Tobacco smoking: Induces CYP1A2 via polycyclic aromatic hydrocarbons; smokers clear caffeine ~40–65% faster.supported

    Polycyclic aromatic hydrocarbons in tobacco smoke induce CYP1A2, leading to faster caffeine clearance. pmid:10427467

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Claim in pharmacology — inconclusiveinconclusiveworking →

  • Claim in pharmacology — inconclusiveinconclusiveworking →

summary19 · 12 ok

  • Claim in summary — inconclusiveinconclusiveworking →

  • Claim in summary — inconclusiveinconclusiveworking →

  • The foundational mechanistic review by Fredholm et al. in 1999 established adenosine antagonism as the primary mediator of caffeine's central effectssupported

    Landmark comprehensive review of caffeine pharmacology in the brain. Covers adenosine antagonism, dopaminergic effects, reinforcement, withdrawal, tolerance. pmid:10049999

  • Current investigational interest centers on caffeine's neuroprotective potential in Parkinson's disease — supported by robust prospective epidemiological data — and its established clinical role in neonatal apnea of prematurity.supported

    Prospective cohort: inverse associations between caffeine intake and Parkinson disease. Prediagnostic caffeine metabolites quantified years before PD onset. wnl.0000000000209201

  • Current investigational interest centers on caffeine's neuroprotective potential in Parkinson's disease — supported by robust prospective epidemiological data — and its established clinical role in neonatal apnea of prematurity.supported

    Caffeine therapy for apnea of prematurity reduces the rate of bronchopulmonary dysplasia in infants with very low birth weight. Landmark RCT establishing caffeine as first-line treatment for neonatal apnea. nejmoa054065

  • Claim in summary — inconclusiveinconclusiveworking →

  • Claim in summary — inconclusiveinconclusiveworking →

  • At doses exceeding 500 mg, secondary mechanisms — phosphodiesterase inhibition and intracellular calcium mobilization — become pharmacologically relevant.supported

    Low-dose caffeine acts as an adenosine A1, A2A, A2B antagonist. High-dose effects have different underlying mechanisms. j.mam.2016.11.011

  • The resulting phenomenology is primarily one of cognitive normalization rather than true enhancement: caffeine restores vigilance, attention, and reaction time most effectively when cognition is degraded by fatigue, sleep deprivation, or stresssupported

    Caffeine should be viewed as a 'cognitive normalizer' not enhancer. Restores memory in sleep-deprived and aged individuals. jad-2010-1408

  • Dose-dependent anxiogenesis is the principal adverse psychological effect, with individuals carrying ADORA2A polymorphisms and those with panic disorder showing heightened vulnerabilitysupported

    Panic disorder patients particularly sensitive to anxiogenic effects. A2A receptor polymorphism influences anxiety threshold. jad-2010-1378

  • Dose-dependent anxiogenesis is the principal adverse psychological effect, with individuals carrying ADORA2A polymorphisms and those with panic disorder showing heightened vulnerabilitysupported

    Systematic review and meta-analysis of caffeine's anxiogenic and panicogenic effects in panic disorder patients. Quantifies magnitude and dose-response relationships. j.genhosppsych.2021.11.005

  • Caffeine has a wide therapeutic index (estimated LD50 ~150–200 mg/kg; lethal dose ~10.5–14 g in a 70 kg adult), but concentrated powder and energy drink products have caused fatalities at doses far below what beverage consumption could deliversupported

    LD50 stated as 150-200 mg/kg; lethal plasma levels ~80-100 ug/mL. Pre-dialysis caffeine level 254 ug/mL. j.ajem.2019.09.018

  • Claim in summary — inconclusiveinconclusiveworking →

  • Caffeine has a wide therapeutic index (estimated LD50 ~150–200 mg/kg; lethal dose ~10.5–14 g in a 70 kg adult), but concentrated powder and energy drink products have caused fatalities at doses far below what beverage consumption could deliversupported

    Energy drinks potentially trigger life-threatening cardiac arrhythmias via highly stimulating ingredients. Documents cases of sudden cardiac arrest in temporal proximity to energy drink consumption. j.hrthm.2024.02.018

  • Claim in summary — inconclusiveinconclusiveworking →

  • Tolerance develops through upregulation of adenosine receptors and functional adaptation of A1-A2A heteromers in the striatum, though wakefulness-promoting effects remain partially preserved even with chronic usesupported

    Caffeine acts on A1-A2A heteromers; chronic caffeine leads to tolerance through modifications in heteromer function. jneurosci.3574-05.2006

  • Tolerance develops through upregulation of adenosine receptors and functional adaptation of A1-A2A heteromers in the striatum, though wakefulness-promoting effects remain partially preserved even with chronic usesupported

    Daily caffeine intake and withdrawal affect circadian rhythms and wake-promotion. Evidence for adaptation after repeated intake. j.pnpbp.2019.109851

  • CYP1A2-mediated metabolism introduces clinically significant variability: fluvoxamine co-administration increases caffeine half-life approximately six-fold, and neonatal CYP1A2 immaturity extends half-life to 65–100 hourssupported

    Fluvoxamine 50-100mg/day increases caffeine half-life from 5h to 31h and reduces total clearance from 107 to 21 ml/min. pmid:8807660

  • Claim in summary — inconclusiveinconclusiveworking →

neuroscience12 · 8 ok

  • Caffeine produces modest hedonic effects (liking) but robust habitual consumption driven by negative reinforcement — the desire to avoid withdrawal-associated fatigue and headache (wanting)supported

    Covers adenosine antagonism, dopaminergic effects, reinforcement, withdrawal, tolerance. pmid:10049999

  • ADORA2A pharmacogenomics: The A2A receptor gene variant influences anxiogenic sensitivity, but the full scope of ADORA2A polymorphism effects on caffeine response — including tolerance development, withdrawal severity, and neuroprotective benefit — is poorly characterized.supported

    A2A receptor polymorphism influences anxiety threshold. jad-2010-1378

  • Claim in neuroscience — inconclusiveinconclusiveworking →

  • By blocking A2A, caffeine enhances D2-mediated dopaminergic transmission — increasing locomotor activity, elevating mood, and producing weak positive reinforcementsupported

    Covers adenosine antagonism, dopaminergic effects, reinforcement, withdrawal, tolerance. pmid:10049999

  • Cunha and Agostinho characterized caffeine as a cognitive normalizer — it restores cognition degraded by sleep deprivation, aging, or stress rather than enhancing performance above rested baseline.supported

    Caffeine should be viewed as a 'cognitive normalizer' not enhancer. Restores memory in sleep-deprived and aged individuals. jad-2010-1408

  • Caffeine blocks this homeostatic sleep signal, producing wakefulness and delaying sleep onsetsupported

    Daily caffeine intake and withdrawal affect circadian rhythms and wake-promotion. j.pnpbp.2019.109851

  • Claim in neuroscience — inconclusiveinconclusiveworking →

  • Claim in neuroscience — inconclusiveinconclusiveworking →

  • Epidemiological data consistently associate habitual caffeine consumption with reduced risk of Parkinson's disease, and less consistently with reduced Alzheimer's disease risksupported

    Longitudinal studies show reduced Parkinson disease risk with caffeine consumption. s1474-4422(16)30230-7

  • Epidemiological data consistently associate habitual caffeine consumption with reduced risk of Parkinson's disease, and less consistently with reduced Alzheimer's disease risksupported

    Non-linear protective relationship between 1-3 cups/day coffee and dementia. Isolated caffeine not clearly protective for AD. d4fo01750a

  • However, Mendelian randomization studies have not confirmed a causal relationship, leaving open whether the association reflects caffeine's direct neuroprotective action, confounding lifestyle factors, or non-caffeine bioactive compounds in coffee and tea.supported

    Suggestive but not definitive evidence for PD protection. nu14091697

  • Claim in neuroscience — inconclusiveinconclusiveworking →

clinical-evidence7 · 7 ok

  • Aidman et al. conducted a double-blind, placebo-controlled study demonstrating that repeated 200 mg caffeine doses during total sleep deprivation disrupted the performance-degrading impact of drowsiness on vigilance tasks — producing performance gains largely independent of subjective sleepiness levelssupported

    50-hour total sleep deprivation protocol; caffeine (200mg x4 doses as chewing gum) produced substantial performance gains largely independent of actual drowsiness levels. s41598-021-83504-6

  • The International Society of Sports Nutrition position stand confirms caffeine as an effective ergogenic aid: it improves endurance performance, time trials, and reaction time at doses of 3–6 mg/kg body weight, with onset approximately 30–60 minutes before exercisesupported

    ISSN position: caffeine improves endurance performance, time trials, reaction time. Effective doses 3-6 mg/kg. Onset 30-60 min before exercise. s12970-020-00383-4

  • The Caffeine for Apnea of Prematurity (CAP) trial (NCT00182312) — a multicenter randomized controlled trial by Schmidt et al. — established caffeine citrate as standard of care for apnea of prematuritysupported

    Landmark RCT establishing caffeine as first-line treatment for neonatal apnea. nejmoa054065

  • Robust epidemiological evidence supports an inverse association between habitual caffeine consumption and Parkinson's disease (PD) risksupported

    Longitudinal studies show reduced Parkinson disease risk with caffeine consumption. s1474-4422(16)30230-7

  • Mendelian randomization analysis by Larsson et al. provided mixed results, with genetically predicted plasma caffeine levels not clearly associated with PD risk, suggesting the epidemiological association may be partially confounded or mediated by non-caffeine coffee components.supported

    Suggestive but not definitive evidence for PD protection. nu14091697

  • Li et al.'s systematic review and meta-analysis of cohort studies found that tea and coffee intake were associated with reduced dementia and Alzheimer's disease (AD) risk, though the extent to which caffeine itself (versus other bioactive compounds) mediates this association remains unresolvedsupported

    Tea consumption associated with decreased dementia risk. Non-linear protective relationship between 1-3 cups/day coffee and dementia. Isolated caffeine not clearly protective for AD. d4fo01750a

  • This supports caffeine's characterization as a cognitive normalizer under fatigued conditions rather than a cognitive enhancer above baseline.supported

    Caffeine should be viewed as a 'cognitive normalizer' not enhancer. jad-2010-1408

pharmacokinetic-detail7 · 4 ok

  • Fluvoxamine is the most clinically significant: even low doses (10–20 mg/day) substantially inhibit caffeine metabolism, and standard therapeutic doses increase caffeine half-life from ~5 hours to ~31 hours with total clearance reduced approximately 5-fold.supported

    Even low therapeutic doses of fluvoxamine significantly inhibit CYP1A2 activity as measured by caffeine metabolic ratio. pmid:11907488

  • Fluvoxamine is the most clinically significant: even low doses (10–20 mg/day) substantially inhibit caffeine metabolism, and standard therapeutic doses increase caffeine half-life from ~5 hours to ~31 hours with total clearance reduced approximately 5-fold.supported

    Fluvoxamine 50-100mg/day increases caffeine half-life from 5h to 31h and reduces total clearance from 107 to 21 ml/min. pmid:8807660

  • Fluvoxamine is the most clinically significant: even low doses (10–20 mg/day) substantially inhibit caffeine metabolism, and standard therapeutic doses increase caffeine half-life from ~5 hours to ~31 hours with total clearance reduced approximately 5-fold.supported

    Fluvoxamine co-administration impairs caffeine clearance and prolongs elimination half-life via CYP1A2 inhibition. pmid:16236038

  • The most comprehensive pharmacokinetic characterization of caffeine derives from Grzegorzewski et al.'s systematic analysis of 141 publications.supported

    Systematic analysis of caffeine pharmacokinetics from 141 publications. fphar.2021.752826

  • Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

  • Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

  • Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

receptor-pharmacology4 · 1 ok

  • Claim in receptor-pharmacology — inconclusiveinconclusiveworking →

  • Claim in receptor-pharmacology — inconclusiveinconclusiveworking →

  • Claim in receptor-pharmacology — inconclusiveinconclusiveworking →

  • Ciruela et al. identified functional A1R-A2AR heteromeric complexes on striatal glutamatergic nerve terminalssupported

    Demonstrates A1R-A2AR heteromers in striatal glutamatergic nerve terminals. jneurosci.3574-05.2006

chemistry3 · 0 ok

  • Claim in chemistry — inconclusiveinconclusiveworking →

  • Claim in chemistry — inconclusiveinconclusiveworking →

  • Claim in chemistry — inconclusiveinconclusiveworking →

comparative-pharmacology3 · 0 ok

  • Claim in comparative-pharmacology — inconclusiveinconclusiveworking →

  • Claim in comparative-pharmacology — inconclusiveinconclusiveworking →

  • Claim in comparative-pharmacology — inconclusiveinconclusiveworking →

legal-status3 · 1 ok

  • The FDA and EFSA have established recommended daily intake limits (400 mg for adults, 200 mg for pregnant women), but these are advisory rather than legally enforced consumption capssupported

    Habitual caffeine up to 400mg/day safe for non-pregnant adults. For pregnant women: up to 200mg/day safe. j.efsa.2015.4102

  • Claim in legal-status — inconclusiveinconclusiveworking →

  • Claim in legal-status — inconclusiveinconclusiveworking →

history2 · 2 ok

  • The first comprehensive pharmacological analysis of caffeine in the brain — covering adenosine antagonism, dopaminergic interactions, reinforcement, tolerance, and factors contributing to its ubiquitous consumption — was published by Fredholm et al. in 1999 in Pharmacological Reviewssupported

    Landmark comprehensive review of caffeine pharmacology in the brain. Covers adenosine antagonism, dopaminergic effects, reinforcement, withdrawal, tolerance. pmid:10049999

  • Clinical application preceded full mechanistic understanding: caffeine citrate has been used therapeutically for neonatal apnea since the 1970s-1980s, with the landmark Caffeine for Apnea of Prematurity (CAP) randomized controlled trial by Schmidt et al. in 2006 establishing caffeine as standard of care and demonstrating reduced bronchopulmonary dysplasia and improved neurodevelopmental outcomes.supported

    Caffeine therapy for apnea of prematurity reduces the rate of bronchopulmonary dysplasia in infants with very low birth weight. Landmark RCT establishing caffeine as first-line treatment for neonatal apnea. nejmoa054065

effects-overview1 · 1 ok

  • In caffeine-naive users, the experience is predominantly one of clean, focused wakefulness with mild mood elevation; in chronic users, much of the perceived benefit represents restoration of a withdrawal-suppressed baseline rather than genuine enhancement above normal functioningsupported

    Caffeine should be viewed as a 'cognitive normalizer' not enhancer. Restores memory in sleep-deprived and aged individuals. jad-2010-1408

Other runs

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3Sources

42 consumed · sorted by year · feeds = sections resting on it

Sources 1 to 30
yearsourcetierstatusfeeds
2026Caffeine WithdrawalRocha Cabrero F, Hamilton RJ, et al. · Nutrientsdoi:10.3390/nu16183048moderateconsumed2 sections
2026The Effect of Caffeine Consumption and Acute Withdrawal on Resting-State fMRI Brain Connectivity, Mood and Cognition.Sevenoaks T, Lancelotte F, Souter N, Stafford L, Rae C, Yeomans M · European Journal of Neurosciencedoi:10.1111/ejn.70511moderateconsumed1 section
2024Association of Coffee Consumption and Prediagnostic Caffeine Metabolites With Incident Parkinson Disease in a Population-Based Cohort.Zhao Y, Lai Y, Konijnenberg H, et al. · Neurologydoi:10.1212/wnl.0000000000209201moderateconsumedcited only
2024Caffeine — PubChem CID 2519PubChem · PubChem (NCBI)pmid:2519moderateconsumed1 section
2024Caffeine history: isolation by Runge 1819, synthesis by Fischer 1895Wikipedia / Inverse.comurl:82c6fbbe1c91abadweakconsumedcited only
2024Caffeine physical properties: melting point, solubility, CASPubChem/NIST/ChemicalBookurl:dd3ceb5d8ca5d8ccweakconsumedcited only
2024Sudden cardiac arrest occurring in temporal proximity to consumption of energy drinks.Martinez KA, Bains S, Neves R, Giudicessi JR, Bos JM, Ackerman MJ · Heart Rhythmdoi:10.1016/j.hrthm.2024.02.018weakconsumed2 sections
2024Tea, coffee, and caffeine intake and risk of dementia and Alzheimer's disease: a systematic review and meta-analysis of cohort studies.Li F, Liu X, Jiang B, et al. · Food & Functiondoi:10.1039/d4fo01750astrongconsumed2 sections
2022Effects of caffeine on anxiety and panic attacks in patients with panic disorder: A systematic review and meta-analysis.Klevebrant L, Frick A · General Hospital Psychiatrydoi:10.1016/j.genhosppsych.2021.11.005strongconsumed2 sections
2022Plasma Caffeine Levels and Risk of Alzheimer's Disease and Parkinson's Disease: Mendelian Randomization Study.Larsson SC, Woolf B, Gill D · Nutrientsdoi:10.3390/nu14091697moderateconsumed2 sections
2021Caffeine may disrupt the impact of real-time drowsiness on cognitive performance: a double-blind, placebo-controlled small-sample study.Aidman E, Balin M, Johnson K, et al. · Scientific Reportsdoi:10.1038/s41598-021-83504-6strongconsumed1 section
2021International society of sports nutrition position stand: caffeine and exercise performance.Guest NS, VanDusseldorp TA, Nelson MT, Grgic J, Schoenfeld BJ, et al. · Journal of the International Society of Sports Nutritiondoi:10.1186/s12970-020-00383-4strongconsumed1 section
2021Pharmacokinetics of Caffeine: A Systematic Analysis of Reported Data for Application in Metabolic Phenotyping and Liver Function Testing.Grzegorzewski J, Bartsch F, Köller A, König M · Frontiers in Pharmacologydoi:10.3389/fphar.2021.752826strongconsumed7 sections
2020Acute intentional caffeine overdose treated preemptively with hemodialysis.Kohl BA, Kaur K, Dincher N, Schumann J, Carachilo T, Komurek C · American Journal of Emergency Medicinedoi:10.1016/j.ajem.2019.09.018weakconsumed2 sections
2020Caffeine-dependent changes of sleep-wake regulation: Evidence for adaptation after repeated intake.Weibel J, Lin YS, Landolt HP, Garbazza C, et al. · Progress in Neuro-Psychopharmacology & Biological Psychiatrydoi:10.1016/j.pnpbp.2019.109851moderateconsumed3 sections
2017Arrhythmogenic effects of energy drinks.Enriquez A, Frankel DS · Journal of Cardiovascular Electrophysiologydoi:10.1111/jce.13210weakconsumed1 section
2017Low, but not high, dose caffeine is a readily available probe for adenosine actions.Fredholm BB, Yang J, Wang Y · Molecular Aspects of Medicinedoi:10.1016/j.mam.2016.11.011moderateconsumed2 sections
2016The epidemiology of Parkinson's disease: risk factors and prevention.Ascherio A, Schwarzschild MA · The Lancet Neurologydoi:10.1016/s1474-4422(16)30230-7strongconsumedcited only
2015Scientific Opinion on the safety of caffeine. EFSA 2015.EFSA Panel on Dietetic Products, Nutrition and Allergies · EFSA Journaldoi:10.2903/j.efsa.2015.4102weakconsumed2 sections
2014Caffeine intake during pregnancy and adverse birth outcomes: a systematic review and dose-response meta-analysis.Greenwood DC, Thatcher NJ, Ye J, Garrard L, et al. · European Journal of Epidemiologydoi:10.1007/s10654-014-9944-xstrongconsumed1 section
2014Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug?Cappelletti S, Piacentino D, Sani G, Aromatario M · Current Neuropharmacologydoi:10.2174/1570159x13666141210215655moderateconsumed3 sections
2014Expression and characterization of purinergic receptors in rat middle meningeal artery--potential role in migraine.Haanes KA, Edvinsson L · PLoS ONEdoi:10.1371/journal.pone.0108782moderateconsumed1 section
2014Regulatory status of caffeine in the United States.Rosenfeld LS, Mihalov JJ, Carlson SJ, Mattia A · Nutrition Reviewsdoi:10.1111/nure.12136moderateconsumed2 sections
2012Caffeine provokes adverse interactions with MDMA and related psychostimulants: mechanisms and mediators.Vanattou-Saîfoudine N, McNamara R, Harkin A · British Journal of Pharmacologydoi:10.1111/j.1476-5381.2012.02065.xmoderateconsumed1 section
2012Characterization of individuals seeking treatment for caffeine dependence.Juliano LM, Evatt DP, Richards BD, Griffiths RR · Psychology of Addictive Behaviorsdoi:10.1037/a0027246moderateconsumed1 section
2012The effects of energy drink in combination with alcohol on performance and subjective awareness.Alford C, Hamilton-Morris J, Verster JC · Psychopharmacologydoi:10.1007/s00213-012-2677-1strongconsumed1 section
2011International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update.Fredholm BB, IJzerman AP, Jacobson KA, Linden J, Müller CE · Pharmacological Reviewsdoi:10.1124/pr.110.003285strongconsumed5 sections
2011Structure of the adenosine A(2A) receptor in complex with ZM241385 and the xanthines XAC and caffeine.Doré AS, Robertson N, Errey JC, et al. · Structuredoi:10.1016/j.str.2011.06.014moderateconsumedcited only
2010Caffeine and adenosine.Ribeiro JA, Sebastião AM · Journal of Alzheimer's Diseasedoi:10.3233/jad-2010-1379moderateconsumedcited only
2010Caffeine, mental health, and psychiatric disorders.Lara DR · Journal of Alzheimer's Diseasedoi:10.3233/jad-2010-1378moderateconsumedcited only
Show all 44 sources — 14 more
Sources 31 to 44
yearsourcetierstatusfeeds
2010Chronic caffeine consumption prevents memory disturbance in different animal models of memory decline.Cunha RA, Agostinho PM · Journal of Alzheimer's Diseasedoi:10.3233/jad-2010-1408moderateconsumedcited only
2006Caffeine therapy for apnea of prematurity.Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W · New England Journal of Medicinedoi:10.1056/nejmoa054065strongconsumed3 sections
2006Presynaptic Control of Striatal Glutamatergic Neurotransmission by Adenosine A1-A2A Receptor HeteromersCiruela F, Casadó V, Rodrigues RJ, Luján R, Burgueño J, et al. · Journal of Neurosciencedoi:10.1523/jneurosci.3574-05.2006moderateconsumed4 sections
2005Fluvoxamine impairs single-dose caffeine clearance without altering caffeine pharmacodynamics.Culm-Merdek KE, von Moltke LL, Harmatz JS, Greenblatt DJ · British Journal of Clinical Pharmacologypmid:16236038strongconsumed2 sections
2005Oxidation of caffeine by CYP1A2: isotope effects and metabolic switching.Regal KA, Kunze KL, Peter RM, Nelson SD · Drug Metabolism and Dispositionpmid:16135658moderateconsumed2 sections
2002Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (CYP1A2) and omeprazole (CYP2C19).Christensen M, Tybring G, Mihara K, et al. · Clinical Pharmacology and Therapeuticspmid:11907488strongconsumed2 sections
1999Actions of caffeine in the brain with special reference to factors that contribute to its widespread use.Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE · Pharmacological Reviewspmid:10049999strongconsumed7 sections
1999Drug interactions with tobacco smoking. An update.Zevin S, Benowitz NL · Clinical Pharmacokineticspmid:10427467moderateconsumed2 sections
1996A fluvoxamine-caffeine interaction study.Jeppesen U, Loft S, Poulsen HE, Brøsen K · Pharmacogeneticspmid:8807660strongconsumed3 sections
1994Biotransformation of caffeine in human liver microsomes from foetuses, neonates, infants and adults.Cazeneuve C, Pons G, Rey E, et al. · British Journal of Clinical Pharmacologypmid:8054245moderateconsumed3 sections
1994Caffeine and sports activity: a review.Nehlig A, Debry G · International Journal of Sports Medicinepmid:7960313moderateconsumed1 section
1994Caffeine dependence syndrome. Evidence from case histories and experimental evaluations.Strain EC, Mumford GK, Silverman K, Griffiths RR · JAMApmid:8089887moderateconsumed1 section
—Searched cross-reference for "Primary ROA discrepancy: seed data says insufflated, evidence review" — no resultsabsenceno results—
—Searched PubMed for "caffeine sleep quality adenosine polysomnography" — no resultsabsenceno results—

4Docket

one filing per activity — decisions, correspondence, reports

  1. 0012026-04-25revisionRevision 1

    Initial LLM generation (v5 pipeline, wiki)

    psx:substance/caffeine/version/1
  2. 0022026-06-04proposal29 value proposals approved together

    one review action inferred from a shared reviewer and instant — the graph records one activity per proposal

    29 items in this filing

    • dose_tier · light
    • dose_tier · common
    • dose_tier · strong
    • dose_tier · heavy
    • timeline · oral · onset
    • timeline · oral · come_up
    • timeline · oral · peak
    • timeline · oral · plateau
    • timeline · oral · resolution
    • timeline · oral · afterglow
    • toxicity
    • dependence · full
    • withdrawal
    • tolerance
    • dosage · oral
    • duration · oral · onset
    • duration · oral · come_up
    • duration · oral · peak
    • duration · oral · offset
    • duration · oral · total
    • duration · oral · aftereffects
    • contraindication · psychiatric
    • contraindication · psychiatric
    • contraindication · cardiovascular
    • contraindication · pregnancy_breastfeeding
    • contraindication · age
    • contraindication · metabolic
    • contraindication · cardiovascular
    psx:substance/caffeine/proposal/dose_tier/bddcbd62-a5e8-483f-b2e1-ae7a30f10e9d
  3. 0032026-06-04publicationPublication — backfill
    psx:substance/caffeine/pub/2f054361-f59f-490c-88b5-e2affe5330f4
  4. 0042026-09-18revisionr1.a1

    brief-overview retired 2026-09-30 (founder): Description reads the essential summary for every substance.

    psx:substance/caffeine/version/2

5Issued documents

what the notice, info card and emergency page said, by hash

Issued documents
documentcontent hashissuedfrom versionsuperseded
info_card0143f403def8f998919fce01…2026-10-19 20:30Revision 1current
emergency777b5863d801327b008f5610…2026-09-04 04:29Revision 1current
info_card471af3eb6a45afd2912e88a9…2026-09-04 04:29Revision 1superseded2026-10-19
noticefb6e5e61c98289464444fa49…2026-09-04 04:29Revision 1current